Epidemiologic data, clinical trials, and studies in laboratory animals have established a relationship between diets rich in saturated fat and cholesterol, atherogenic lipoproteins, and development of atherosclerosis. As a consequence of this information, diets low in cholesterol and saturated fat have been recommended. Adherence to low cholesterol diets imposes severe restrictions on the intake of eggs with major nutritional and economic implications. However, blanket recommendations for the U.S. population with regard to egg consumption may be challenged because of heterogeneity in the genetic makeup influencing an individual's response to dietary cholesterol. The goals of this proposal are i) to define the principal mechanism(s) which determine the reaction of the lipid metabolism to dietary cholesterol, and ii) to develop meaningful tests to identify hypo- and hyperresponders to excess dietary cholesterol. Our central hypothesis is that cholesterol homeostasis is intimately linked to the catabolism of chylomicrons in that ineffective clearance of chylomicrons fails to inhibit endogenous cholesterol synthesis and hepatic lipoprotein production and leads to accumulation of atherogenic lipoproteins in the circulation and, ultimately, to atherosclerosis. To test this hypothesis, hypo- and hyperresponders to excess dietary cholesterol will be identified by screening of normolipemic adults. In these subjects, adaptive responses of the plasma lipid transport system subsequent to 4 diets differing in cholesterol content (300 mg vs. 1700 mg/day) and P/S ratio (0.4 vs. 2.5) will be studied under strict metabolic and dietary control. Major fasting lipoprotein classes will be characterized and quantified, and activities of lipoprotein and hepatic lipase, LCAT, and cholesteryl ester transfer protein will be measured at the end of each dietary period. Catabolism of alimentary and endogenous lipoproteins will be assessed by measuring the concentration of TG in plasma, and of retinyl ester and apoB-48/apoB-100 in the d less than 1.019 lipoproteins in the course of lipemia after a standardized oral fat load. Clearance of dietary fat will be related to inhibition of endogenous cholesterol synthesis as determined by plasma mevalonate levels and HMG- CoA reductase activity in mononuclear blood cells. Postprandial lipoproteins will be characterized physicochemically, and their interaction with macrophages will be determined as an index of atherogenicity. The relationship of chylomicron catabolism to hepatic lipoprotein production will be studied in the cholesterol fed rabbit. These studies should enhance our understanding of how lipid metabolism is affected by dietary cholesterol.